Heparin is a commonly used anticoagulant from biological sources such as intestinal mucosa. In the presence of heparin, the inactivation of thrombin by anti-thrombin III (AT-III) is greatly accelerated, involving changes in both the conformation of heparin and AT-III on complexation. Thrombin regulates the last step in the blood coagulation cascade. The prime function of thrombin is the cleavage of fibrinogen to generate fibrin monomers, which form an insoluble gel, a fibrin clot, by cross-linking.
The structural features of heparin that are required for interacting AT-III have been subject to various investigations. There are parts in the heparin polymer which show only low affinity for AT-III, whereas other parts were found to be more important for binding to AT-III. Studies of fragmented heparin have finally resulted in the identification of a pentasaccharide fragment accounting for the minimal high-affinity structure that binds to AT-III (see e.g. Physiological Reviews, 71 (2), 488/9, 1991). In this high-affinity fragment eight sulfate groups are present. Four of the sulfate groups were found to be essential for binding to AT-III (Advances in Carbohydrate Chemistry and Biochemistry; Vol. 43; Eds. R. S. Tipson, D. Horton; Publ. Harcourt Brace Jovanovich; B. Casu (pages 51-127), paragraph 6), whereas the other further attribute to higher affinity. This finding was confirmed in synthetic analogues of the pentasaccharide fragment (see e.g. Agnew. Chem. 32 (12), 1671-1818, 1993).
The identification of the high-affinity pentasaccharide fragment inspired the preparation of synthetic analogues thereof. Small synthetic carbohydrate molecules of the glycosaminoglycan type were found to be potent and selective anti-Xa inhibitors. See for instance European patent 84,999. Later filed patents/patent applications showed that many variants of these molecules have similar and even higher activities and further improved pharmacological properties, such as the glycosaminoglycan-related carbohydrate derivatives disclosed in EP 529,715 and EP 454,220. These carbohydrate derivatives are devoid of the characteristic functional groups of glycosaminoglycans: free hydroxyl groups, N-sulfate and N-acetyl groups. Further, all of the pentasaccharides disclosed in these latter patent applications carry at least seven sulfate groups. In the field of antithrombotic oligosaccharide derivatives it was thus generally assumed that at least seven sulfate groups are required in pentasaccharide compounds in order to obtain clinically acceptable levels of antithrombotic activity.
Unexpectedly, however, a class of glycosaminoglycan-related carbohydrate derivatives has now been found having only four to six sulfate groups and which still display significant clinically effective antithrombotic activity. In addition, the compounds of this invention show fewer side effects. For example, bleeding risks are reduced and the low sulfate content of the compounds does not give rise to heparin-induced thrombocytopenia (HIT) [HIT is a severe side effect, which may be the cause of the death of a patient]. Further, compounds of this invention have a biological half-life which allows once-a-day-treatment. Once-a-day-treatment may be considered to be more favourable than, for example, once-a-week-treatment, allowing quick adaptation of the medical treatment is the condition of a patient requires so. Also hospital logistics are easier with one-a-day-treatment, as no complex dosing schemes are required for the treatment of the patients.
Thus, the compounds of the invention display an unexpected and delicately balanced pharmacological profiles.